A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome, AIDS) and degeneration of the central and peripheral nervous system. A common feature of retrovirus replications is reverse transcriptase to generate DNA copies of HIV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothylmidine or AZT. Cyclopropaneacetylene (CPA) is a key raw material for the preparation of an inhibitor of HIV reverse transcriptase, which is known as DMP-266 having a chemical name of (-)6-chloro-4-cyclopropylenthynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxanzin-2-one.
The synthesis of DMP-266 and structurally similar reverse transcriptase inhibitors are disclosed in U.S. Pat. No. 5,519,021, and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et. al., Tetrahedron Letters 1995, 36, 8937-8940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
In addition, various aspects of the synthesis of DMP-266 have been disclosed in United States Patents. U.S. Pat. No. 5,663,467 discloses a synthesis of CPA involving cyclization of 5-halo-1-pentyne in base. U.S. Pat. No. 5,856,492 discloses a synthesis of a chiral mediator, and U.S. Pat. No. 5,922,864 discloses an efficient method to prepare DMP-266 by a cyclization reaction. A process for making chiral alcohol is published on Jul. 16, 1998 in PCT Publication No. WO 98/30543. Several methods have been described in the published literature for preparation of cyclopropaneacetylene. C. E. Hudson and N. L. Bauld, J. Am. Chem. Soc. 94:4, p. 1158 (1972); J. Salaun, J. Org. Chem. 41:7, p. 1237 (1976); and W. Schoberth and M. Hanack, Synthesis p. 703 (1972), disclose methods for the preparation of cyclopropylacetylene by dehydrohalogenating 1-cyclopropyl-1,1-dichloroethane. Miltzer, H. C. et al., Synthesis, 998 (1993) disclose a method for preparation of cyclopropylalkenes by halogenating an enolether, reacting the alkyl 1,2-dihaloether with propargyl magnesium bromide, and cyclizing to give a 2-alkoxy-1-ethynylcyclopropane. F. A. Carey and A. S. Court, J. Org. Chem., Vol. 37, No. 12, p. 1926 (1972) disclose the use of a modified Wittig-Homer olefin synthesis for organic transformations. D. J. Peterson, J. Org. Chem., Vol. 20C, No. 33, p. 780 (1968) describes the application of olefination to make vinyl sulfides and H. Takeshita and T. Hatsui, J. Org. Chem. Vol. 43, No. 15, p. 3083 (1978) disclose the use of potassium 3-aminopropylamide in base-catalyzed prototropic reactions.
However, the currently available ways to prepare CPA, for example synthesizing CPA from 5-chloro-1-pentyne, are not efficient in a large-scale production of CPA, and often have problems with impurities in the final product. As a result, there is a need for an alternative practical way to prepare CPA.
Therefore, it is an object of the present invention to provide a more efficient way to produce CPA, which involves a novel catalytic decarboxylation process.